Non-typhoidal Salmonella serotypes are a leading cause of food-borne infections worldwide, with Salmonella enterica serotypes Typhimurium and Enteritidis being isolated most frequently. In immunocompetent individuals, non-typhoidal Salmonella serotypes cause a localized gastroenteritis with low mortality rates. However, non-typhoidal Salmonella serotypes cause a life-threatening bacteremia in immunocompromised patients. The precise immune mechanisms that enable an immunocompetent host to prevent bacterial dissemination and bacteremia are poorly understood. Our long-range goal is to understand the pathogenesis of S. typhimurium infections in immunocompromised patients. The objectives of this application are to investigate the importance of the IL-22/IL-17 axes in preventing S. typhimurium dissemination. Our central hypothesis is that the cytokines IL-17 and IL-22 orchestrate an intestinal epithelial response that aids in containing S. typhimurium at its site of entry, the intestinal mucosa. We plan to test our hypothesis and fulfill the objectives of this application by establishing an animal model for functional studies on the intestinal barrier to S. typhimurium infection and by characterizing epithelial responses orchestrated by IL-17 and IL-22 in vitro and in vivo. The proposed work is innovative because it establishes new model systems and new theoretical concepts for studying the development of bacteremia in immunocompromised patients. It is our expectation that the outcome of the proposed studies will identify the IL-17/IL-22-axes as an arm of the mucosal response that plays a key role in limiting bacterial dissemination from the intestine. This outcome will be significant, because it will identify novel targets for therapeutic intervention in immunocompromised patients. PUBLIC HEALTH RELEVANCE: While non-typhoidal Salmonella serotypes cause a localized gastroenteritis in immunocompetent patients, immunocompromised individuals develop a life-threatening bacteremia. Bacteremia with non-typhoidal Salmonella serotypes is currently a leading cause of hospital admissions and a leading cause of death in Sub-Saharan Africa. Due to the absence of animal models to study Salmonella bacteremia in immunocompromised individuals, our understanding of defects in mucosal barrier function that are responsible for bacterial dissemination is still incomplete. Research proposed in this application will support the pioneering studies needed to establish the models and concepts needed to fill this gap in knowledge.